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Edema , Estenosis de la Válvula Pulmonar , Escroto , Humanos , Masculino , Escroto/patología , Escroto/diagnóstico por imagen , Estenosis de la Válvula Pulmonar/diagnóstico por imagen , Estenosis de la Válvula Pulmonar/complicaciones , Edema/etiología , Edema/diagnóstico por imagen , Edema/patología , Edema/diagnóstico , Diagnóstico Diferencial , Válvula Pulmonar/diagnóstico por imagen , Válvula Pulmonar/anomalías , Válvula Pulmonar/patologíaRESUMEN
INTRODUCTION: Abnormal placental cord insertions (APCIs) are significant risk factors for pregnancy complications, encompassing marginal cord insertion (MCI), velamentous cord insertion (VCI), and vasa previa (VP). While ultrasound is the primary imaging modality, its accuracy can be limited by factors such as maternal obesity and fetal positioning. Complementary to ultrasound, magnetic resonance imaging (MRI) offers a more precise visualization of the fetus, placenta, and umbilical cord relationships. This study aims to investigate the diagnostic value of prenatal magnetic resonance imaging (MRI) for APCIs compared with prenatal ultrasound. METHODS: We retrospectively collected data from 613 patients who underwent prenatal placental ultrasound and MRI. Of those who were confirmed as APCIs through surgery or pathology, the prenatal MRI features were compared with prenatal ultrasound. The diagnostic efficacy of prenatal MRI and ultrasound for APCIs was assessed based on the clinicopathological findings. RESULTS: Fifty-six patients were confirmed as APCIs by surgery or pathology, comprising 31 marginal cord insertions (MCIs), 18 velamentous cord insertions (VCIs), 5 vasa previa (VP) cases, and 2 VCI cases combined with VP. Ultrasound examination showed 55.36 % sensitivity (31/56) and 98.38 % specificity (486/494) in diagnosing APCIs, whereas MRI demonstrated 87.50 % sensitivity (49/56) and 98.88 % specificity (531/537). CONCLUSION: For APCIs complicated by placental location or morphological abnormalities, MRI demonstrates superior diagnostic efficacy compared to ultrasound in late pregnancy.
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Imagen por Resonancia Magnética , Placenta , Ultrasonografía Prenatal , Cordón Umbilical , Humanos , Embarazo , Femenino , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Adulto , Cordón Umbilical/diagnóstico por imagen , Cordón Umbilical/anomalías , Cordón Umbilical/patología , Placenta/diagnóstico por imagen , Placenta/patología , Ultrasonografía Prenatal/métodos , Vasa Previa/diagnóstico por imagen , Enfermedades Placentarias/diagnóstico por imagen , Enfermedades Placentarias/patología , Diagnóstico Prenatal/métodos , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: This retrospective study aimed to investigate treatment patterns and outcomes in patients with NSCLC harboring EGFR20ins in China. EGFR20ins mutations are associated with poor responses to EGFR-TKIs, and limited real-world data exist regarding the efficacy of various treatment modalities. METHODS: In this retrospective, single-center study, treatment outcomes, including PFS and ORR, were evaluated for different treatment regimens based on imaging assessments. The impact of mutation heterogeneity on treatment efficacy was also explored. RESULTS: Data from 302 patients diagnosed with NSCLC with EGFR20ins were analyzed. EGFR-TKI monotherapy demonstrated suboptimal PFS compared to platinum-based chemotherapy in the first-line setting (3.00 m vs. 6.83 m, HR = 3.674, 95%CI = 2.48-5.44, p < 0.001). Platinum plus pemetrexed plus bevacizumab combination therapy showed improved PFS and ORR compared to platinum plus pemetrexed (7.50m vs. 5.43 m, HR = 0.593, 95%CI = 0.383-0.918, p = 0.019). In later-line treatments, monotherapy with EGFR-TKIs or ICIs exhibited suboptimal efficacy. The specific EGFR20ins subtype, A763_Y764insFQEA, showed favorable responses to EGFR-TKIs in real-world settings. CONCLUSIONS: This large-scale real-world study provides valuable insights into the treatment patterns and outcomes of NSCLC patients with EGFR20ins mutations in China. These findings contribute to the understanding of EGFR20ins treatment and provide real-world benchmark for future clinical trials and drug development.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Exones , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Femenino , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , China , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Adulto , Pemetrexed/uso terapéutico , Pemetrexed/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutagénesis Insercional , Mutación , Anciano de 80 o más Años , Pueblos del Este de AsiaRESUMEN
The Ophioglossaceae family, one of the oldest orders of extant ferns, exhibits diverse morphological and chromosomal characteristics. This study presents the first complete plastome sequence of thermal adder's-tongue fern (Ophioglossum thermale), a species renowned for its antioxidant properties in traditional Chinese medicine. Our analyses revealed 27 simple sequence repeats (SSRs) in the plastome, with variations in SSR frequencies compared to related genera. Our phylogenetic analyses placed O. thermale within the Ophioglossum s.s. clade, supporting previous studies and suggesting polyphyly within the genus Ophioglossum based on the sensu PPG I system. The enlarged noncoding regions in fern organelles (ENRFOs) resulting from foreign DNA insertions in O. thermale were identified in the ycf2-trnH and trnT-trnfM regions, similar to other Ophioglossum species. ENRFOs were found at the LSC and SSC, but not in IRs in Ophioglossaceae. Consequently, foreign DNA insertions and lineage-specific SSRs shed light on plastome evolution in the Ophioglossaceae family.
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INTRODUCTION: To date, there have been no studies conducted on the development of interosseous muscles (IO) in the human hand. This study aimed to investigate the development of these muscles in order to clarify their terminal insertions and their relationship with the metacarpophalangeal joints. METHODS: Serial sections of 25 human specimens (9 embryos and 16 fetuses) between the 7th and 14th weeks of development, sourced from the Collection of the Department of Anatomy and Embryology at UCM Faculty of Medicine, were analyzed bilaterally using a conventional optical microscope. RESULTS: Our findings revealed that, during the 7th week of development, the metacarpophalangeal interzone mesenchyme extended into the extensor apparatus of the fingers. Furthermore, we observed that the joint capsule and the tendon of the IO derive from the articular interzone mesenchyme. By the end of the 7th week, corresponding to Carnegie stage 21, the myotendinous junction appeared, initiating cavitation of the metacarpophalangeal joint. During the fetal period, the terminal insertions of the IO were identified: both the dorsal interosseous (DI) and palmar interosseous (PI) muscles insert into the metacarpophalangeal joint capsule and establish a connection with the volar plate located at the base of the proximal phalanx and the extensor apparatus. Some muscle fibers also attach to the joint capsule at the level of the proximal synovial cul-de-sac. The functional implications of these findings are discussed within this work. CONCLUSION: This study provides the first detailed description of the development of the interosseous muscles in the human hand.
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BACKGROUND: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown. METHODS: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation. RESULTS: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response. CONCLUSIONS: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Exones , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Mutagénesis Insercional , Mutación , /uso terapéuticoRESUMEN
BACKGROUND: Although amivantamab has shown clinical benefits for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertions, its cost-effectiveness requires further investigation. AIM: To evaluate the cost-effectiveness of amivantamab plus chemotherapy for the treatment of NSCLC patients with EGFR exon 20 insertions from the United States payer perspective. METHOD: A partitioned survival model was developed based on the data from the PAPILLON trial. Costs were derived from the pricing files of Medicare and Medicaid Services and published literature, and utility values were derived from previous studies. A 3% annual discount rate was applied to both costs and outcomes. The primary outcome was the incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis, probabilistic sensitivity analysis and scenario analysis, were conducted to test the model stability. RESULTS: Amivantamab plus chemotherapy yielded an additional 1.12 quality-adjusted life years (QALYs) while increasing costs by $483,769.50 relative to the chemotherapy regimen, leading to an ICER of $432,401.16/QALY. The combination of amivantamab with chemotherapy was not cost effective at a threshold of $150,000/QALY. In the scenario analysis, the results showed that the ICERs were $263,680.69/QALY and $418,416.35/QALY when different utility values and 10-year time horizons were adopted, respectively. For PSA, the probability that amivantamab plus chemotherapy would be cost-effective was 0% if the willingness-to-pay (WTP) threshold was $150,000/QALY. CONCLUSION: Amivantamab plus chemotherapy is unlikely to be a cost-effective option for NSCLC patients with EGFR exon 20 insertions. Reducing the cost of amivantamab may produce favorable economic outcomes.
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Flexible needle insertion procedures are common in minimally-invasive surgeries for diagnosing and treating prostate cancer. Bevel-tip needles provide physicians the capability to steer the needle during long insertions to avoid vital anatomical structures in the patient and reduce post-operative patient discomfort. To provide needle placement feedback to the physician, sensors are embedded into needles for determining the real-time 3D shape of the needle during operation without needing to visualize the needle intra-operatively. Through expansive research in fiber optics, a plethora of bio-compatible, MRI-compatible, optical shape-sensors have been developed to provide real-time shape feedback, such as single-core and multicore fiber Bragg gratings. In this paper, we directly compare single-core fiber-based and multicore fiber-based needle shape-sensing through similarly constructed, four-active area sensorized bevel-tip needles inserted into phantom and ex-vivo tissue on the same experimental platform. In this work, we found that for shape-sensing in phantom tissue, the two needles performed identically with a p-value of 0.164 > 0.05, but in ex-vivo real tissue, the single-core fiber sensorized needle significantly outperformed the multicore fiber configuration with a p-value of 0.0005 < 0.05. This paper also presents the experimental platform and method for directly comparing these optical shape sensors for the needle shape-sensing task, as well as provides direction, insight and required considerations for future work in constructively optimizing sensorized needles.
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Antibody diversification is essential for an effective immune response, with somatic hypermutation (SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase (AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions (indels). These mutational outcomes contribute to antibody affinity maturation. The mechanisms responsible for generating point mutations and indels involve the base excision repair (BER) and mismatch repair (MMR) pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard, translesion synthesis (TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies (bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.
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BACKGROUND: Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins), an uncommon mutation in non-small cell lung cancer (NSCLC), can induce poor patient response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the clinical features and prognosis of patients with EGFR ex20ins are not clearly understood. This study investigated the clinical characteristics and prognosis of advanced NSCLC patients with EGFR ex20ins. METHODS: Advanced NSCLC patients treated at Fujian Cancer Hospital were consecutively recruited from June 1, 2014 to December 20, 2021 and retrospectively examined. EGFR ex20ins was identified by polymerase chain reaction (PCR) or next-generation sequencing (NGS). The clinical characteristics, treatment methods, and patient outcomes were retrieved from the hospital database. The progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. RESULTS: Fourteen mutation subtypes of EGFR ex20ins were identified in the 24 enrolled patients, with EGFR ex20ins mutation more prevalent in non-smoking women. A763_Y764insFQEA and A767_V769dup (12.5% for both) were the most common mutation subtypes. Notably, no significant differences in PFS and OS were found between the first-line targeted therapy group [PFS: 257 days, 95% confidence interval (CI): 116-397 days; OS: not reached] and chemotherapy-based combination therapy group (PFS: 182 days, 95% CI: 156-207 days; OS: 998 days, 95% CI: 674-1321 days). TP53 mutation was the commonest concomitant mutation (62%), followed by EGFR amplification (25%). Chemotherapy combined with immunotherapy improved the prognosis of patients with high PD-L1 expression. CONCLUSION: For NSCLC patients with EGFR ex20ins, limited therapeutic benefits can be gleaned from either EGFR-TKIs or chemotherapy-based combination therapy.
EGFR-TKIs have limited efficacy in NSCLC patients with EGFR ex20ins. Combining chemotherapy with immunotherapy may represent a promising treatment approach for individuals with positive ex20ins and high PD-L1 expression.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Exones , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Masculino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Pronóstico , Receptores ErbB/genética , Estudios Retrospectivos , Anciano , Exones/genética , Mutación , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Supervivencia sin Progresión , Mutagénesis InsercionalRESUMEN
Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides "regional AF" (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as "rAF-hi" indels. Notably, a high percentage of rare indels were "rAF-hi", with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels' parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.
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Frecuencia de los Genes , Mutación INDEL , Humanos , AlgoritmosRESUMEN
The single-unit monomer insertion (SUMI), derived from living/controlled polymerization, can be directly functionalized at the end or within the chain of polymers prepared by living/controlled polymerization, offering potential applications in the preparation of polymers with complex architectures. Many scenarios demand the simultaneous incorporation of monomers suitable for different polymerization methods into complex polymers. Therefore, it becomes imperative to utilize SUMI technologies with diverse mechanisms, especially those that are compatible with each other. Here, we reported the orthogonal SUMI technique, seamlessly combining radical and cationic SUMI approaches. Through the careful optimization of monomer and chain transfer agent pairs and adjustments to reaction conditions, we can efficiently execute both radical and cationic SUMI processes in one pot without mutual interference. The utilization of orthogonal SUMI pairs facilitates the integration of radical and cationic reversible addition-fragmentation chain transfer (RAFT) polymerization in various configurations. This flexibility enables the synthesis of diblock, triblock, and star polymers that incorporate both cationically and radically polymerizable monomers. Moreover, we have successfully implemented a mixing mechanism of free radicals and cations in RAFT step-growth polymerization, resulting in the creation of a side-chain sequence-controlled polymer brushes.
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Carbon-chain dendritic polymers hold unique properties and promising applications. However, synthesizing carbon-chain dendrimers, beyond conjugated ones, remains a challenge. Here, the use of the iterative single unit monomer insertion technique for synthesizing 2.5 generation partial-carbon-chain dendrimers (G2.5) is described, utilizing bismaleimide as the core, a maleimide-trithiocarbonate conjugate as the branching unit, and indene as the spacer unit, following a divergent growth strategy. The optimized conditions for synthesizing the maleimide-trithiocarbonate branching unit are a bismaleimide to trithiocarbonate ratio of 5:1 and a reaction time of 30 min. The structures are verified using 1H nuclear magnetic resonance, gel permeation chromatography, and matrix-assisted laser desorption/ionization-time of flight mass spectra. A four-arm star polymer is then synthesized using the G2.5 as the core. This synthesis of a partial-carbon-chain dendrimer establishes a foundational step toward creating all-carbon-chain ones and may open new application avenues in material science.
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Carbono , Dendrímeros , Dendrímeros/química , Dendrímeros/síntesis química , Carbono/química , Estructura Molecular , Maleimidas/química , Maleimidas/síntesis química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Polimerizacion , Polímeros/química , Polímeros/síntesis químicaRESUMEN
Transposable elements (TEs) are a major force in the evolution of plant genomes. Differences in the transposition activities and landscapes of TEs can vary substantially, even in closely related species. Interspecific hybridization, a widely employed technique in tomato breeding, results in the creation of novel combinations of TEs from distinct species. The implications of this process for TE transposition activity have not been studied in modern cultivars. In this study, we used nanopore sequencing of extrachromosomal circular DNA (eccDNA) and identified two highly active Ty1/Copia LTR retrotransposon families of tomato (Solanum lycopersicum), called Salsa and Ketchup. Elements of these families produce thousands of eccDNAs under controlled conditions and epigenetic stress. EccDNA sequence analysis revealed that the major parts of eccDNA produced by Ketchup and Salsa exhibited low similarity to the S. lycopersicum genomic sequence. To trace the origin of these TEs, whole-genome nanopore sequencing and de novo genome assembly were performed. We found that these TEs occurred in a tomato breeding line via interspecific introgression from S. peruvianum. Our findings collectively show that interspecific introgressions can contribute to both genetic and phenotypic diversity not only by introducing novel genetic variants, but also by importing active transposable elements from other species.
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ADN Circular , Genoma de Planta , Retroelementos , Solanum lycopersicum , Secuencias Repetidas Terminales , Solanum lycopersicum/genética , ADN Circular/genética , Fitomejoramiento , Secuenciación de Nanoporos/métodos , Introgresión Genética , Análisis de Secuencia de ADN/métodos , ADN de Plantas/genéticaRESUMEN
BACKGROUND: Familial hypercholesterolemia (MIM: PS143890) is a genetic disorder characterized by an increase in blood cholesterol. LDLR is one of the genes which their defect contributes to the disorder. Affected individuals may carry a heterozygous variant or homozygous/compound heterozygous variants and those with biallelic pathogenic variants present more severe symptoms. METHOD: We report an Egyptian family with familial hypercholesterolemia. Both the proband and parents have the disorder while a sibling is unaffected. Exome sequencing was performed to identify the causal variant. RESULTS: LINE-1 insertion in exon 7 of LDLR was identified. Both parents have a heterozygous variant while the proband has a homozygous variant. The unaffected sibling did not carry the variant. DISCUSSION: This insertion may contribute to the high prevalence of hypercholesterolemia in Egypt and the finding underscores the importance of implementing mobile element insertion caller in routine bioinformatics pipeline.
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Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Biología Computacional , Egipto , Exones , Hiperlipoproteinemia Tipo II/genética , Elementos de Nucleótido Esparcido LargoRESUMEN
The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1-4.
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Repeticiones de Minisatélite , Páncreas Exocrino , Humanos , Repeticiones de Minisatélite/genética , Animales , Ratones , Páncreas Exocrino/metabolismo , Páncreas Exocrino/enzimología , Células HEK293 , Mutagénesis Insercional/genética , Alelos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/enzimología , Frecuencia de los Genes , Masculino , Femenino , Lipasa/genéticaRESUMEN
This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary's illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary.
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Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.
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Calcineurina , Neoplasias , Humanos , Calcineurina/genética , Neoplasias/genética , Mutación/genética , Carcinogénesis , Mutación Missense/genéticaRESUMEN
Insertions in the epidermal growth factor receptor (EGFR) exon 20 (Ex20Ins) are the third most incident mutations in non-small cell lung cancer (NSCLC). The hypervariable nature of these driver mutations hinders their identification by traditional polymerase chain reaction (PCR)-based methods, requiring a comprehensive sequencing approach to detect all possible insertions. The prognosis of patients with EGFR Ex20Ins is similar to those with wild-type NSCLC, since no targeted drugs are approved in the first-line setting, and platinum-based chemotherapy is currently the front-line treatment. However, the new generation of drugs currently being tested in first and post-platinum settings will likely change the management of this entity. Here, we summarize the latest data on EGFR Ex20Ins molecular characteristics, patient profile, identification challenges, and emerging therapies to help lung clinicians face a growing treatment landscape.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Mutación , Exones/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Evaluation of the cystic duct anatomy prior to bile duct or gallbladder surgery is important, to decrease the risk of bile duct injury. This study aimed to clarify the frequency of cystic duct variations and the relationship between them. METHODS: Data of 205 patients who underwent cholecystectomy after imaging at Sada Hospital, Japan, were analyzed. The Chi-square test was used to analyze the relationships among variations. RESULTS: The lateral and posterior sides of the bile duct were the two most common insertion points (92 patients, 44.9%), and the middle height was the most common insertion height (135 patients, 65.9%). Clinically important variations (spiral courses, parallel courses, low insertions, and right hepatic duct draining) relating to the risk of bile duct injury were observed in 24 patients (11.7%). Regarding the relationship between the insertion sides and heights, we noticed that the posterior insertion frequently existed in low insertions (75.0%, P < 0.001) and did not exist in high insertions. In contrast, the anterior insertion coexisted with high and never low insertions. Spiral courses have two courses: anterior and posterior, and anterior ones were only found in high insertion cases. CONCLUSIONS: The insertion point of the cystic duct and the spiral courses tended to be anterior or lateral superiorly and posterior inferiorly. Clinically significant variations in cystic duct insertions are common and surgeons should be cautious about these variations to avoid complications.